Type-I (based on classification of Coombs and Gell) allergic diseases, such as bronchial asthma, atopic dermatitis and allergic rhinitis, have been understood to be mainly caused by IgE-mediated release of chemical mediators from mast cells and basophils.
Recent immunological studies have shown, however, that tissue-damaging chronic inflammatory reactions, mainly by T-cells and eosinophils, are closely related to various allergic diseases. The International Asthma Committee report announced in 1992 no longer describes bronchial asthma as simple immediate-type hypersensitivity, but a chronic inflammatory disease due mainly to T-cells and eosinophils. This naturally has led clinicians to attach greater importance to the control of chronic inflammation, which underlies airway obstruction, in its treatment. Anti-inflammatory therapy, mainly using steroids, is recommended as therapy of first choice.
Infiltration of eosinophils into tissues is a common feature of allergic diseases such as bronchial asthma and atopic dermatitis, as well as so-called eosinophilic diseases. Eosinophil granule-derived basic proteins such as major basic protein (MBP), eosinophil cationic protein (ECP) and eosinophil-derived peroxidase (EPO) have great tissue-damaging effects, causing tissue destruction and marked inflammatory reactions. Eosinophils serve as effector cells in inflammatory reactions. As mentioned above, recent studies have shown that the cytokine IL-5 produced by activated T-cells play an important role in eosinophils' infiltration into tissues and activation (H. Okudaira et al, Allergy and Clinical Immunology News, 6/1, 19-25 (1994); A. Mori et al, International Archives Allergy and Immunology 104, 32-35 (1994)!. IL-5 is a cytokine with a molecular weight of about 13 KDa and is mainly produced by activated T-cells. In humans, it has been shown to specifically affect eosinophils and enhance their growth, differentiation and cytotoxicity (effector function), as well as to enhance the release of mediators (such as leukotriene, MBP, etc.) by them (Lopez A. F. et al, Journal of Experimental Medicine, 167: 219-224, 1988). Many investigators have shown in animal models that neutralization of IL-5 results in marked inhibition of bronchial asthma reactions and infiltration of cells such as eosinophils (Egan R. W., 15th International Allergic Society Meeting Report and the 20th CIA Meeting Report).
The inventors have conducted immunological studies on the pathology of bronchial asthma and found that IL-5 production by CD4-positive T-cells in peripheral blood is significantly greater in both atopic and non-atopic bronchial asthma patients than in healthy volunteers. A close correlation was found between therapeutic efficacy and IL-5 production in asthma patients (A. Mori, et al., International Immunology 7: 449-457, 1995). The inventors showed in vitro experiments that steroids, FK506 (an immunosuppressive agent) and cyclosporine A dose-dependently inhibit the production of IL-5 by T-cells (A. Mori, et al, International Immunology 7: 449-457, 1995). In the clinical experience of the inventors, symptomatic bronchial asthma patients show marked improvement in clinical symptoms and laboratory tests within 1 week after treatment with steroids (inhalation). These improvements are associated with decreases in blood eosinophil counts and reduced production of IL-5 by peripheral CD4-positive T-cells. Furthermore, symptoms such as skin eruption and itching drastically improve within several days after local administration of FK506 in very severe atopic dermatitis patients. Production of IL-5 by peripheral CD4-positive T-cells is also markedly inhibited in these patients. The inventors therefore thought that IL-5 production inhibitors should be useful for treating allergic diseases associated with eosinophilic inflammation.
Screening of drugs for ability to inhibit IL-5 is expected to be useful for efficiently discovering those which are clinically effective for allergic and eosinophilic diseases (A. Mori, et al, Environmental Dermatology, 1, 42-54 (1994); A. Mori, et al, International Archives of Allergy and Immunology, 104, 32-35 (1994)!. The inventors have demonstrated the importance of IL-5 production by T-cells in the onset of allergic diseases in both basic and clinical medical studies. In the belief that inhibition of IL-5 production by T-cells would be very effective for controlling eosinophilic inflammation, we investigated various immunosuppressive agents both in vitro and in vivo. Steroids, which strongly inhibit IL-5 production in vitro, have long been used as the only drugs with remarkable efficacy for severe bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. As a result, the development of non-steroidal IL-5 inhibitors which inhibit eosinophilic inflammation by inhibiting IL-5 production like steroids but are devoid of adverse reactions has been desired.
As a result of various studies to achieve this objective, the inventors discovered that macrolide antibiotics produced by actinomycetes (shown by formula 1) markedly inhibit the production of IL-5 by human T-cells.